ALBANY, N.Y. (March 4, 2005) -- In experiments
with mice, a team of scientists including UAlbany
chemist Eric Block have found the first evidence
of neurons responsive to social odors, using
a new analytical approach to isolate one of
these social odors -- a novel sulfur-containing
chemical in urine that enables mice to distinguish
between the sexes -- defining maleness in the
mice.

The neurons were discovered in the mice's
main olfactory system, a group of brain structures
used to process smell. Until now, it has been
believed that most chemical social signals
in mammals are detected by a different system,
the accessory olfactory system, that is absent
in humans. The researchers said their findings
that mice also use their main olfactory system
to detect social signals suggest that humans
too may communicate via social odors, because humans possess the same set of
brain regions.

The researchers, led by Howard Hughes Medical
Institute investigator Lawrence Katz at Duke
University Medical Center and Distinguished
Professor of Chemistry Eric Block at the University
at Albany, State University of New York, together
with Da Yu Lin in Katz’s lab and Dr. Shao-Zhong Zhang in Block’s
lab, published their findings February 20, 2005, in the online edition of the
journal Nature.

The researchers used a new combination of
analytical techniques to isolate volatile compounds
from mouse urine and trace their effects on
the neural odor-processing circuitry. Besides
mapping the odor effects in the brain, they
also isolated a novel sulfur-containing chemical
that may enable mice to identify another individual
as male or female. They demonstrated that the presence of this chemical in
male mouse urine substantially enhances the
attractiveness of males to female mice. Importantly,
this chemical is only found in male mouse urine,
not in urine from female mice or in castrated
male mice that lack sex hormones.

“These represent the first comprehensive study of how a complex social
stimulus like urine is represented in the olfactory bulb, which is a system that
both humans and other mammals possess,” said Katz. “The results were
very clear and really quite surprising. We found that in a complex mixture like
urine, which has at least a hundred compounds in it, an individual nerve cell
in the olfactory bulb acted as a detector for just one of those compounds. This
finding will help settle a continuing debate among scientists studying the olfactory
system -- whether olfactory neurons are broadly tuned, responding to many different
compounds, or whether they act as olfactory feature detectors,” said Katz.

The researchers’ mapping revealed that only a very small area of the olfactory
bulb responded to the urine volatiles, said Katz. In particular, Lin and Katz
noticed that one component present in only infinitesimal amounts and only in
male urine nevertheless evoked a particularly strong response in the mouse neurons.
Their analysis suggested the presence of a novel sulfur-containing compound.
To confirm the compound’s identity, UAlbany's Eric Block, an authority
in the chemistry of organic compounds of sulfur (such as those from garlic, onions
and mushrooms), and postdoctoral fellow Zhang synthesized possible candidate
molecules, and the researchers tested their effects on neuronal responses. This
analysis revealed the compound to be (methylthio)methanethiol, or MTMT. The researchers
found MTMT in the urine of intact male mice, but not in urine from females or
castrated males, and found that the females were much more attracted to urine
containing MTMT, but not to urine that did not contain the compound.

Block said, “It was quite amazing to us that this stinky little molecule,
having only ten atoms and present at levels corresponding to only a few molecules
mixed with a billion others in a mixture as complex as urine, was able to elicit
a strong positive response from female mice. We can now add mice to the list
of other animals -- skunks, ants, hamsters, mink, hyenas -- that use small sulfur
molecules for social signaling and defensive purposes.” Block said that
there is “an important additional piece of information conveyed by the
urine sulfur compound, namely that small variations in the levels of MTMT could
indicate to other mice the freshness of the urine. This is because other sulfur-containing
compounds in mouse urine, or even oxygen in air, can react with MTMT and thereby
gradually decrease MTMT concentrations over time.”

Katz said, “There are persistent reports about the influence of odorant
communications in all sorts of behavior in humans -- mothers recognizing infants,
wives recognizing husbands and of course the influence of perfumes and colognes.
Since we’ve found that mice -- which are well known to use odors for social
communications -- do so using the main olfactory system, this strongly suggests
that sex-specific volatile chemicals in our bodily secretions could also be detected
by similar circuitry.” In further studies, Katz and his colleagues are
using a vast array of odors, both synthetic and natural, to decipher the olfactory “code” by
which the brain constructs elaborate olfactory scenes from combinations of odorants.
They also seek to understand how mice combine information from multiple odors
to recognize other individual mice, much as humans recognize other individuals
by their faces. Such studies may yield insights into the formation of human perception,
which enables recognition of specific objects in the environment by combining
multiple components, be they visual, auditory or olfactory, said Katz.

“The question is how do you know a rose is different from a skunk, or how
a merlot is different from a cabernet?” asked Katz. “It’s because
we have a sophisticated olfactory discrimination system that relies on detecting
and integrating information from a distinctive set of chemicals."

“One of the important questions remaining to be answered is specifically
how a volatile small molecule such as MTMT is recognized by the receptor proteins
found in the olfactory bulb. A sustained team effort is needed to solve this
riddle, the solution to which will greatly advance our knowledge of this least
understood of all of our senses, the sense of smell,” said Block.

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